Over 20 million people in the US have diabetes mellitus (DM). Of patients with DM, type II accounts for 90-95% of all diagnosed cases. Many diabetic patients develop significant gastrointestinal symptoms, with up to 60% of longstanding diabetics suffering from delayed gastrointestinal transit, diarrhea or constipation. Chronic constipation associated with type II DM, in addition to diarrhea and incontinence, is increasingly regarded as having serious effects on patient quality of life. Current treatments of Gl complications have considerable side-effects and therefore a greater understanding of the disease would provide novel targets for treatment and possible cure. The current dogma is that Gl disorders associated with type II DM is a consequence of an enteric neuropathy. In the present proposal we have investigated the mechanisms underlying Gl disorders in type II DM. Rather than an enteric neuropathy, we provide evidence that interstitial cells of Cajal that generate pacemaker activity and are critical for enteric motor neurotransmission are disrupted in type II DM. The finding that ICC are affected by type II DM introduces a novel hypothesis that Gl dysmotility and neuromuscular dysfunction associated with this disease could, in part, be due to changes in ICC pacemaker activity and the 'in-series' relationship that exists between enteric motor nerves and intramuscular ICC. The loss of Kit-labeling of ICC associated with DM in humans and animal models has been attributed to cell death though the apoptotic signaling pathway or transdifferentiation. We investigated whether ICC homeodynamics are affected by increased apoptosis or decreased cell division. The mechanism(s) of cell growth and expansion of ICC populations will be investigated in type II DM tissues allotransplanted with ICC. In summary, this proposal will provide important information about the defects in ICC networks (which are involved in pacemaker activity and in enteric neuromuscular transmission witin the Gl tract) that occur in the Gl tracts of patients with type II DM. New information will be obtained about the processes underlying the disruption of neuromuscular function in the Gl tracts of animal models with DM, that may be causative in delayed intestinal transit, constipation or diarrhea in human patients. RELEVANCE (See instructions): Relevance to gastrointestinal motility disorders associated with type II diabetes.